Neurogenesis is a vital process in the brains of animals and humans, whereby new nerve cells are continuously generated throughout the life span of the organism. The newly born cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain. Neurogenesis is known to persist throughout adulthood in two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and give rise to new functional neurons and glial cells (for review Gage Mol Psychiatry. 2000 May; 5(3):262-9). It has been shown that a variety of factors can stimulate adult hippocampal neurogenesis, e.g., adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent learning and anti-depressants (Yehuda. J Neurochem. 1989 July; 53(1):241-8, van Praag. Proc Natl Acad Sci USA. 1999 Nov. 9; 96(23):13427-31, Brown. J Eur J Neurosci. 2003 May; 17(10):2042-6, Gould. Science. 1999 Oct. 15; 286(5439):548-52, Malberg. J Neurosci. 2000 Dec. 15; 20(24):9104-10, Santarelli. Science. 2003 Aug. 8; 301(5634):805-9). Other factors, such as adrenal hormones, stress, age and drugs of abuse negatively influence neurogenesis (Cameron. Neuroscience. 1994 July; 61(2):203-9, McEwen. Neuropsychopharmacology. 1999 October; 21(4):474-84, Kuhn. J Neurosci. 1996 Mar. 15; 16(6):2027-33, Eisch. Am J Psychiatry. 2004 March; 161(3):426).
Renin and angiotensin are components of the renin-angiotensin system (RAS) and the renin-angiotensin-aldosterone system (RAAS). The two systems are commonly considered to function in regulating long-term blood pressure and blood volume in the body, with the RAAS acting in part through the release of aldosterone from the adrenal cortex.
Both systems have renin and angiotensin in common, where renin proteolytically cleaves inactive angiotensinogen to form the decapeptide angiotensin I (AI). Angiotensin-converting enzyme (ACE) then cleaves AI to form the octapeptide angiotensin II (AII). Of the two angiotensins, AII has been observed to be more potent. AII acts as a vasoconstrictor to raise arterial blood pressure and decrease blood flow. AII also acts on the adrenal cortex, which leads to the release of aldosterone. In turn, aldosterone acts in the kidney to cause resorption of sodium and water from urine. The result in an increase in the fluid volume of blood.
The two systems are activated following blood loss or a drop in blood pressure. Other components of the systems are the AII receptor(s) that mediate AII activity. Angiotensin receptors are G protein-coupled receptors which bind AII as a ligand. Subtypes of the receptors include AT1 and AT2, both of which bind AII, and the AT3 and AT4 receptors.
Both the receptors and ACE have been the targets of manipulation to treat hypertension (high blood pressure) and other conditions. AII receptor antagonists, also referred to as angiotensin receptor blockers or ARBs, AT1-receptor antagonists, or sartans, are used to antagonize AII activity by preventing AII interactions with AII receptor(s). ACE inhibitors are used to lower AII formation. Additional information is available, for example, in the review by Jackson, et al. in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, pp. 733-754 (New York: McGraw-Hill, 1996).
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